In his junior year, O'Byrne entrenched himself as a top defender within Cornell's ECAC leading defence corps to be selected as a First Team All-Ivy player.[5] Despite missing nearly a month to injury, O'Byrne led all Big Red defenceman with 7 goals and 13 points in 28 games and was named in the ECAC Third-Team before losing in a rematch to Harvard in the ECAC Championship.[6] O'Byrne was selected by Cornell Coach Mike Schäfer as an alternate captain, but decided to forgo his senior year to begin his professional career signing a two-year entry level contract with the Montreal Canadiens on August 9, 2006.[7]

After attending his first Montreal training camp, he was assigned to American Hockey League affiliate, the Hamilton Bulldogs, for the 2006–07 season. As a stay-at-home defensive-defenceman, Ryan produced just 12 assists in 80 games with the Bulldogs, waiting until the playoffs to score his first professional goals. In scoring his first goal, an opening series clinching goal over the Rochester Americans, he helped the Bulldogs advance to the Conference Semi-finals. In the Championship Final, he then produced his second game-winning goal a game three win over the Hershey Bears en route to claiming the Calder Cup.[8]

In the following 2007–08 season, O'Byrne resumed playing with Hamilton before he was later recalled to the Canadiens and made his NHL debut, recording two assists, in a 4-2 victory over the Boston Bruins on December 6, 2007.[9] Ryan missed a month of the season after suffering a broken thumb, before returning to health and scoring his first NHL goal in a 6-4 defeat to the San Jose Sharks on March 4, 2008.[10] He finished the season, while splitting time between Hamilton and Montreal, to finish with 33 games.

O'Byrne was then re-signed to a three-year contract with the Canadiens on July 16, 2008.[11] He made the Canadiens opening night roster for the 2008–09 season, and was used as a reserve defenceman. With two stints in the AHL, O'Byrne appeared in 37 games for five assists, however his season was highlighted and gained the most attention on November 24, 2008, when he unintentionally tied the score with an own goal in the last minutes of a game against the New York Islanders, in which the Canadiens would go on to lose 4-3 in overtime.[12] In his second game of the 2009–10 campaign with the Canadiens, Ryan suffered a knee injury causing him to miss the next 20 games. Upon his return, O'Byrne established himself as a regular within the defence corps. On December 4, 2009, he changed his jersey number to 20 due to retiring of the number 3 in honour of Emile Bouchard for the Canadiens Centennial celebrations. Similar to Ray Bourque's homage to Phil Esposito in Boston, Ryan wore the number 20 jersey underneath his number 3 jersey and as a surprise, unveiled his new number during the banner hanging and presented Bouchard his jersey as a token of being the last to wear the number 3 for the Canadiens.[13] O'Byrne finished his first full NHL season, appearing in a career high 55 games and 13 post-season games as the Canadiens reached the Eastern Conference finals.

To begin the 2010–11 season, O'Byrne was relegated as a depth defenceman on the team's blueline. In the final year of his contract and unable to establish a position he was traded by the Canadiens to the Colorado Avalanche for forward prospect Michael Bournival on November 11, 2010.[14] In his first game with the Avalanche, Ryan recorded a career high in ice time in a 5-1 win over the Columbus Blue Jackets on November 12, 2010.[15]

In the midst of the 2012–13 season and in the final year of his contract at the trade deadline, O'Byrne was dealt by the Avalanche to the Toronto Maple Leafs in exchange for a fourth-round pick in the 2014 NHL Entry Draft on April 3, 2013.[16] On April 8, 2013, O'Byrne scored his first goal as a Maple Leaf.

After experiencing a first round defeat to the Boston Bruins with the Leafs, O'Byrne was not offered a new contract and was released to free agency. With limited NHL interest, O'Byrne agreed to his first contract abroad, signing a two-year contract with Czech based HC Lev Praha of the Kontinental Hockey League on September 2, 2013.[17] In the 2013–14 season, O'Byrne enjoyed a largely successful season in Prague as a mainstay stay-at-home defenseman. In 43 games he contributed with 2 goals and 9 points before helping Lev Praha advance to the Gagarin Cup finals in the playoffs.

O'Byrne's intention to fulfil the second year of his contract was terminated as Lev Praha declared bankruptcy and folded immediately in the off-season. On July 7, 2014, he opted to remain in Europe but moved to Switzerland in signing a one-year contract with HC Ambrì-Piotta of the NLA.[18]

On February 11, 2008, O'Byrne and teammate Tom Kostopoulos were arrested with force outside a Tampa Bay, Florida nightclub following the team's rookie dinner for a purse-snatching incident.[19] He was charged that night with grand theft after police found him with a woman's purse in one hand making a call with her cellphone in the other. Kostopoulos was charged with resisting the officers after he was told to back off while they were dealing with O'Byrne. Both were eventually released on bail—O'Byrne's was $2,000, Kostopoulos' was $500.[20] The charges against Kostopoulos were dropped a few weeks later, while those against O'Byrne were dropped in July 2008, after he apologized to the victim and conceded to do community service in Canada.[21]